Efficacy and Safety of LCZ696 in Comparison to Olmesartan in Asian Patients With Essential Hypertension

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01785472
• Collaborator: (none)
• Enrollment: 1,438
• Locations: 50
• Arms: 3
• Duration (Months): 16
• Patients Per Site: 28.8
• Patients Per Site Per Month: 1.8

Study Details

Study Description

Brief Summary

This study will assess the efficacy and safety of multiple doses of LCZ696 compared to olmesartan in Asian patients with essential hypertension

Condition or Disease	Intervention/Treatment	Phase
Essential Hypertension	Drug: LCZ696; Drug: Olmesartan; Drug: Placebo of LCZ696; Drug: Placebo of Olmesartan	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1438 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multi-center, Randomized, Double-blind, Active-controlled, 8-week Study to Evaluate the Efficacy and Safety of LCZ696 in Comparison to Olmesartan in Patients With Essential Hypertension
• Study Start Date: Apr 1, 2013
• Actual Primary Completion Date: Aug 1, 2014
• Actual Study Completion Date: Aug 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LCZ696 200 mg Patients will be treated with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily(qd) for eight weeks along with placebo of Olmesartan 20 mg capsule once daily.	Drug: LCZ696; LCZ696 200 mg tablet; Drug: Placebo of LCZ696; Placebo tablet of LCZ696 200 mg once daily; Drug: Placebo of Olmesartan; Placebo capsule of olmesartan 20 mg once daily
Experimental: LCZ696 400 mg Patients will start with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily (qd) for one week, thereafter all patients in the treatment group will be up-titrated to two LCZ696 200 mg tablets (400 mg of LCZ696) qd for the remaining seven weeks. Placebo of Olmesartan 20 mg capsule once daily also will be taken.	Drug: LCZ696; LCZ696 200 mg tablet; Drug: Placebo of LCZ696; Placebo tablet of LCZ696 200 mg once daily; Drug: Placebo of Olmesartan; Placebo capsule of olmesartan 20 mg once daily
Active Comparator: Olmesartan 20 mg Patients will be treated with Olmesartan 20 mg for eight weeks once daily along with placebo of LCZ696 tablets once daily.	Drug: Olmesartan; Olmesartan 20 mg capsule; Drug: Placebo of LCZ696; Placebo tablet of LCZ696 200 mg once daily

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) Between LCZ696 200 mg Versus Olmesartan 20 mg [baseline, 8 weeks]

   Sitting BP measurements will be performed at screening through end of study at every visit. Four separate sitting BP measurements will be obtained with a full two minute interval between measurements.

Secondary Outcome Measures

1. Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) Between LCZ696 400 mg Versus Olmesartan 20 mg [baseline, 8 weeks]

   Sitting BP measurements will be performed at screening through end of study at every visit. Four separate sitting BP measurements will be obtained with a full two minute interval between measurements

2. Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) Between LCZ696 200, and LCZ696 400 mg Versus Olmesartan 20 mg [baseline, 8 weeks]

   Sitting BP measurements were performed at screening through the end of the study at every study visit. A negative change from baseline indicates improvement

3. Change From Baseline in Office Pulse Pressure (msPP) [baseline, 8 weeks]

   Four separate sitting BP measurements should be obtained with a full two minute interval between measurements.

4. Change From Baseline in Mean 24-hour Ambulatory Blood Pressure [baseline, 8 weeks]

   In this analysis, mean 24 hour ambulatory systolic blood pressure maSBP, mean 24 hour ambulatory diastolic blood pressure maDBP, daytime and nightime maSBP and maDBP will be reported. Ambulatory blood pressure monitoring over a 24 hour period will be conducted at two time points during the study.

5. Sub-group Analysis for Change From Baseline in Mean Ambulatory Systolic Blood Pressure in Dippers. [baseline, 8 weeks]

   Twenty four hour ABPM was performed twice duirng the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. Dippers were defined as participants who showed a decrease of at least 10% in maSBP during the night (10pm-6am) compared with the daytime level. A negative change from baseline indicates improvement

6. Sub-group Analysis for Change From Baseline in Mean Ambulatory Diastolic Blood Pressure in Dippers. [baseline, 8 weeks]

   Twenty four hour ABPM was performed twice duirng the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. Dippers were defined as participants who showed a decrease of at least 10% in maSBP during the night (10pm-6am) compared with the daytime level. A negative change from baseline indicates improvement

7. Sub-group Analysis for Change From Baseline in Mean Ambulatory Systolic Blood Pressure in Non-dippers. [baseline, 8 weeks]

   Twenty four hour ABPM was performed twice duirng the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. Dippers were defined as participants who showed a decrease of at least 10% in maSBP during the night (10pm-6am) compared with the daytime level. A negative change from baseline indicates improvement

8. Sub-group Analysis for Change From Baseline in Mean Ambulatory Diastolic Blood Pressure in Non-dippers. [baseline, 8 weeks]

   Twenty four hour ABPM was performed twice duirng the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. Dippers were defined as participants who showed a decrease of at least 10% in maSBP during the night (10pm-6am) compared with the daytime level. A negative change from baseline indicates improvement

9. Number of Patients Achieving Successful Blood Pressure Control [8 weeks]

   Successful blood pressure control is defined as msSBP <140 mmHg and msDBP <90 mmHg.

10. Change From Baseline in Ambulatory Pulse Pressure [baseline, 8 weeks]

    Ambulatory pulse pressure (PP) is calculated by hourly ambulatory SBP and hourly ambulatory DBP over a 24-hour period.

11. Number of Responders [baseline, 8 weeks]

    Responders are patients with msSBP response (<140 mmHg or ≥20 mmHg reduction from baseline) and msDBP response (<90 mmHg or ≥10 mmHg reduction from baseline)

12. Number of Patients With Adverse Events, Serious Adverse Events, and Death as Assessment of Safety and Tolerability [baseline, 8 weeks]

    Participants were monitored for adverse events, serious adverse events and deaths throughout the study.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with mild-to-moderate hypertension, untreated or currently taking antihypertensive therapy.

• Treated patients (using antihypertensive treatments within 4 weeks prior to Visit 1) must have an msSBP≥150 mmHg and <180 mmHg at the randomization visit (Visit 201) and msSBP≥140 mmHg <180 mmHg at the visit immediately preceding Visit 201 (Visit 102 or 103).

• Untreated patients (newly diagnosed with essential hypertension or having a history of hypertension but have not been taking any antihypertensive drugs for at least 4 weeks prior to Visit 1) must have an msSBP≥150 mmHg and <180 mmHg at both Visit 1 and Visit

• Patients must have an absolute difference of ≤15 mmHg in msSBP between Visit 201 and the immediately preceding visit.

Exclusion Criteria:

• Patients with severe hypertension (msDBP ≥110 mmHg and or msSBP ≥180 mmHg).

• History of angioedema, drug-related or otherwise, as reported by the patient.

• History or evidence of a secondary form of hypertension, including but not limited to any of the following: renal parenchymal hypertension, renovascular hypertension (unilateral or bilateral renal artery stenosis), coarctation of the aorta, primary hyperaldosteronism, Cushing's disease, pheochromocytoma, polycystic kidney disease, and drug-induced hypertension.

• Patients who previously entered a LCZ696 study and had been randomized or enrolled into the active drug treatment epoch.

Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Beijing	Beijing	China	100044
2	Novartis Investigative Site	Chongqing	Chongqing	China	400010
3	Novartis Investigative Site	Chongqing	Chongqing	China	400042
4	Novartis Investigative Site	Fuzhou	Fujian	China
5	Novartis Investigative Site	Guangzhou	Guangdong	China	510080
6	Novartis Investigative Site	Nanning	Guangxi	China	530021
7	Novartis Investigative Site	Shijiazhuang	Hebei	China	050000
8	Novartis Investigative Site	Harbin	Heilongjiang	China	150001
9	Novartis Investigative Site	Wuhan	Hubei	China	430030
10	Novartis Investigative Site	Changsha	Hunan	China	410003
11	Novartis Investigative Site	Nanjing	Jiangsu	China	210009
12	Novartis Investigative Site	Suzhou	Jiangsu	China	215006
13	Novartis Investigative Site	Nanchang	Jiangxi	China	330006
14	Novartis Investigative Site	Shenyang	Liaoning	China	110016
15	Novartis Investigative Site	Shanghai	Shanghai	China	200072
16	Novartis Investigative Site	Shanghai	Shanghai	China	200120
17	Novartis Investigative Site	Xi'an	Shanxi	China	710004
18	Novartis Investigative Site	Xi'an	Shanxi	China	710061
19	Novartis Investigative Site	Tianjin	Tianjin	China	300121
20	Novartis Investigative Site	Hangzhou	Zhejiang	China	310013
21	Novartis Investigative Site	Beijing		China	100020
22	Novartis Investigative Site	Beijing		China	100029
23	Novartis Investigative Site	Beijing		China	100034
24	Novartis Investigative Site	Fuzhou		China	350001
25	Novartis Investigative Site	Shanghai		China	200025
26	Novartis Investigative Site	Shanghai		China	200031
27	Novartis Investigative Site	Shanghai		China	200032
28	Novartis Investigative Site	Tianjin		China	300142
29	Novartis Investigative Site	Hong Kong		Hong Kong
30	Novartis Investigative Site	Seoul	Korea	Korea, Republic of	03080
31	Novartis Investigative Site	Seoul	Korea	Korea, Republic of	05505
32	Novartis Investigative Site	Seoul	Korea	Korea, Republic of	06591
33	Novartis Investigative Site	Seoul	Korea	Korea, Republic of	08308
34	Novartis Investigative Site	Koyang	Kyunggi	Korea, Republic of	410-719
35	Novartis Investigative Site	Quezon City	Manila	Philippines	1100
36	Novartis Investigative Site	Quezon City		Philippines	1102
37	Novartis Investigative Site	Singapore		Singapore	169609
38	Novartis Investigative Site	Tainan 704	Taiwan ROC	Taiwan	70403
39	Novartis Investigative Site	Kaohsiung		Taiwan	807
40	Novartis Investigative Site	Kaohsiung		Taiwan	82445
41	Novartis Investigative Site	New Taipei City		Taiwan	23561
42	Novartis Investigative Site	Taichung		Taiwan	40447
43	Novartis Investigative Site	Taipei County		Taiwan	22060
44	Novartis Investigative Site	Taipei		Taiwan	10002
45	Novartis Investigative Site	Taipei		Taiwan	110
46	Novartis Investigative Site	Yun-Lin		Taiwan	640
47	Novartis Investigative Site	Khon Kaen	THA	Thailand	40002
48	Novartis Investigative Site	Bangkok		Thailand	10700
49	Novartis Investigative Site	Chiang Mai		Thailand	50200
50	Novartis Investigative Site	Rajathevee		Thailand	10400

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01785472
• Other Study ID Numbers: CLCZ696A2315; CLCZ696A2315
• First Posted: Feb 7, 2013
• Last Update Posted: Dec 29, 2016
• Last Verified: Nov 1, 2016

• Keywords provided by Novartis Pharmaceuticals: Essential hypertension; LCZ696
• Additional relevant MeSH terms: Hypertension; Essential Hypertension; Olmesartan; Olmesartan Medoxomil; Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	Olmesartan 20 mg
Arm/Group Description	Patients will be treated with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily(qd) for eight weeks along with placebo of Olmesartan 20 mg capsule once daily.	Patients will start with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily (qd) for one week, thereafter all patients in the treatment group will be up-titrated to two LCZ696 200 mg tablets (400 mg of LCZ696) qd for the remaining seven weeks. Placebo of Olmesartan 20 mg capsule once daily also will be taken.	Patients will be treated with Olmesartan 20 mg for eight weeks once daily along with placebo of LCZ696 tablets once daily.
Period Title: Overall Study
STARTED	479	473	486
Full Analysis Set (FAS)	479	472	484
Safety Set (SAF)	478	472	484
COMPLETED	455	454	464
NOT COMPLETED	24	19	22

Baseline Characteristics

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	Olmesartan 20 mg	Total
Arm/Group Description	Patients will be treated with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily(qd) for eight weeks along with placebo of Olmesartan 20 mg capsule once daily.	Patients will start with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily (qd) for one week, thereafter all patients in the treatment group will be up-titrated to two LCZ696 200 mg tablets (400 mg of LCZ696) qd for the remaining seven weeks. Placebo of Olmesartan 20 mg capsule once daily also will be taken.	Patients will be treated with Olmesartan 20 mg for eight weeks once daily along with placebo of LCZ696 tablets once daily.	Total of all reporting groups
Overall Participants	479	472	484	1435
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	57.5 (10.17)	58.1 (9.71)	57.4 (10.14)	57.7 (10.01)
Gender (Count of Participants)
Female	227 47.4%	229 48.5%	223 46.1%	679 47.3%
Male	252 52.6%	243 51.5%	261 53.9%	756 52.7%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) Between LCZ696 200 mg Versus Olmesartan 20 mg
Description	Sitting BP measurements will be performed at screening through end of study at every visit. Four separate sitting BP measurements will be obtained with a full two minute interval between measurements.
Time Frame	baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

Only participants, who had both baseline and week 8 values, were included in the analysis. The FAS included all randomized participants who received study medication and had post baseline BP assessments

Arm/Group Title	LCZ696 200 mg	Olmesartan 20 mg
Arm/Group Description	Patients will be treated with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily(qd) for eight weeks along with placebo of Olmesartan 20 mg capsule once daily.	Patients will be treated with Olmesartan 20 mg for eight weeks once daily along with placebo of LCZ696 tablets once daily.
Measure Participants	477	479
Least Squares Mean (Standard Error) [mmHg]	-20.48 (0.61)	-18.15 (0.61)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 200 mg, Olmesartan 20 mg
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The statistical test was made at a one-sided significance level of 0.025.
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	least Square Means net difference
	Estimated Value	-2.33
	Confidence Interval	() 95%; -4.00 to -0.66
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.85
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) Between LCZ696 400 mg Versus Olmesartan 20 mg
Description	Sitting BP measurements will be performed at screening through end of study at every visit. Four separate sitting BP measurements will be obtained with a full two minute interval between measurements
Time Frame	baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

Only participants, who had both baseline and week 8 values, were included in the analysis. The FAS included all randomized participants who received study medication and had post baseline BP assessments

Arm/Group Title	LCZ696 400 mg	Olmesartan 20 mg
Arm/Group Description	Patients will start with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily (qd) for one week, thereafter all patients in the treatment group will be up-titrated to two LCZ696 200 mg tablets (400 mg of LCZ696) qd for the remaining seven weeks. Placebo of Olmesartan 20 mg capsule once daily also will be taken.	Patients will be treated with Olmesartan 20 mg for eight weeks once daily along with placebo of LCZ696 tablets once daily.
Measure Participants	469	479
Least Squares Mean (Standard Error) [mmHg]	-21.67 (0.62)	-18.15 (0.61)

3. Secondary Outcome

Title	Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) Between LCZ696 200, and LCZ696 400 mg Versus Olmesartan 20 mg
Description	Sitting BP measurements were performed at screening through the end of the study at every study visit. A negative change from baseline indicates improvement
Time Frame	baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

Participants from the full analysis set (FAS), who had both baseline and week 8 values, were included in the analysis. The FAS included all participants who received study medication and had post baseline BP assessments

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	Olmesartan 20 mg
Arm/Group Description	Patients will be treated with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily(qd) for eight weeks along with placebo of Olmesartan 20 mg capsule once daily.	Patients will start with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily (qd) for one week, thereafter all patients in the treatment group will be up-titrated to two LCZ696 200 mg tablets (400 mg of LCZ696) qd for the remaining seven weeks. Placebo of Olmesartan 20 mg capsule once daily also will be taken.	Patients will be treated with Olmesartan 20 mg for eight weeks once daily along with placebo of LCZ696 tablets once daily.
Measure Participants	477	469	479
Mean (Standard Error) [mmHg]	-8.10 (0.37)	-8.80 (0.38)	-6.86 (0.37)

4. Secondary Outcome

Title	Change From Baseline in Office Pulse Pressure (msPP)
Description	Four separate sitting BP measurements should be obtained with a full two minute interval between measurements.
Time Frame	baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

Participants from the full analysis set (FAS), who had both baseline and endpoint were included in the analysis. The FAS included all participants who received study medication and had post baseline BP assessments

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	Olmesartan 20 mg
Arm/Group Description	Patients will be treated with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily(qd) for eight weeks along with placebo of Olmesartan 20 mg capsule once daily.	Patients will start with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily (qd) for one week, thereafter all patients in the treatment group will be up-titrated to two LCZ696 200 mg tablets (400 mg of LCZ696) qd for the remaining seven weeks. Placebo of Olmesartan 20 mg capsule once daily also will be taken.	Patients will be treated with Olmesartan 20 mg for eight weeks once daily along with placebo of LCZ696 tablets once daily.
Measure Participants	477	469	479
Least Squares Mean (Standard Error) [mmHg]	-12.35 (0.42)	-12.93 (0.43)	-11.25 (0.42)

5. Secondary Outcome

Title	Change From Baseline in Mean 24-hour Ambulatory Blood Pressure
Description	In this analysis, mean 24 hour ambulatory systolic blood pressure maSBP, mean 24 hour ambulatory diastolic blood pressure maDBP, daytime and nightime maSBP and maDBP will be reported. Ambulatory blood pressure monitoring over a 24 hour period will be conducted at two time points during the study.
Time Frame	baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

A subset of participants, who participated in ambulatory blood pressure monitoring, was analyzed

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	Olmesartan 20 mg
Arm/Group Description	Patients will be treated with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily(qd) for eight weeks along with placebo of Olmesartan 20 mg capsule once daily.	Patients will start with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily (qd) for one week, thereafter all patients in the treatment group will be up-titrated to two LCZ696 200 mg tablets (400 mg of LCZ696) qd for the remaining seven weeks. Placebo of Olmesartan 20 mg capsule once daily also will be taken.	Patients will be treated with Olmesartan 20 mg for eight weeks once daily along with placebo of LCZ696 tablets once daily.
Measure Participants	188	184	182
maSBP	-12.07 (0.49)	-12.76 (0.49)	-10.26 (0.49)
maDBP	-6.36 (0.31)	-6.82 (0.31)	-5.61 (0.31)

6. Secondary Outcome

Title	Sub-group Analysis for Change From Baseline in Mean Ambulatory Systolic Blood Pressure in Dippers.
Description	Twenty four hour ABPM was performed twice duirng the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. Dippers were defined as participants who showed a decrease of at least 10% in maSBP during the night (10pm-6am) compared with the daytime level. A negative change from baseline indicates improvement
Time Frame	baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

A subset of participants, who participated in ambulatory blood pressure monitoring, was analyzed

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	Olmesartan 20 mg
Arm/Group Description	Patients will be treated with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily(qd) for eight weeks along with placebo of Olmesartan 20 mg capsule once daily.	Patients will start with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily (qd) for one week, thereafter all patients in the treatment group will be up-titrated to two LCZ696 200 mg tablets (400 mg of LCZ696) qd for the remaining seven weeks. Placebo of Olmesartan 20 mg capsule once daily also will be taken.	Patients will be treated with Olmesartan 20 mg for eight weeks once daily along with placebo of LCZ696 tablets once daily.
Measure Participants	55	79	74
Hour 1	-13.22 (16.506)	-15.02 (14.578)	-9.07 (17.597)
Hour 2	-17.24 (20.423)	-18.11 (15.343)	-13.95 (19.247)
Hour 3	-14.99 (19.378)	-16.83 (16.312)	-14.51 (18.436)
Hour 4	-13.09 (19.460)	-16.37 (18.710)	-14.63 (18.824)
Hour 5	-11.19 (19.376)	-18.88 (16.636)	-14.64 (21.177)
Hour 6	-13.66 (16.785)	-19.19 (17.771)	-11.54 (21.885)
Hour 7	-11.74 (21.552)	-18.07 (19.748)	-11.74 (24.674)
Hour 8	-13.84 (17.365)	-16.12 (16.696)	-12.99 (20.555)
Hour 9	-16.33 (16.437)	-15.64 (18.915)	-13.33 (18.360)
Hour 10	-13.81 (17.670)	15.13 (18.014)	-10.89 (19.814)
Hour 11	-12.98 (16.856)	-15.93 (19.022)	-7.66 (18.816)
Hour 12	-8.99 (17.913)	-15.54 (20.397)	-10.51 (19.516)
Hour 13	-12.46 (18.694)	-13.28 (17.014)	-11.49 (18.587)
Hour 14	-9.64 (17.001)	-12.33 (16.449)	-6.66 (17.906)
Hour 15	-7.73 (17.362)	-10.12 (14.433)	-7.81 (15.383)
Hour 16	-4.92 (14.788)	-12.82 (13.386)	-4.40 (15.974)
Hour 17	-10.20 (15.780)	-12.43 (14.397)	-7.19 (14.937)
Hour 18	-9.84 (15.789)	-11.70 (13.799)	-8.90 (14.907)
Hour 19	-8.94 (12.283)	-12.20 (15.012)	-5.76 (16.029)
Hour 20	-8.03 (19.411)	-15.04 (14.647)	-4.83 (15.953)
Hour 21	-9.47 (16.984)	-14.33 (13.585)	-9.97 (16.552)
Hour 22	-12.62 (17.527)	-17.20 (14.304)	-9.95 (18.490)
Hour 23	-9.23 (20.068)	-16.63 (15.752)	-14.09 (25.454)
Hour 24	-8.43 (15.330)	-15.76 (17.392)	-12.71 (15.199)

7. Secondary Outcome

Title	Sub-group Analysis for Change From Baseline in Mean Ambulatory Diastolic Blood Pressure in Dippers.
Description	Twenty four hour ABPM was performed twice duirng the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. Dippers were defined as participants who showed a decrease of at least 10% in maSBP during the night (10pm-6am) compared with the daytime level. A negative change from baseline indicates improvement
Time Frame	baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

A subset of participants, who participated in ambulatory blood pressure monitoring, was analyzed

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	Olmesartan 20 mg
Arm/Group Description	Patients will be treated with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily(qd) for eight weeks along with placebo of Olmesartan 20 mg capsule once daily.	Patients will start with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily (qd) for one week, thereafter all patients in the treatment group will be up-titrated to two LCZ696 200 mg tablets (400 mg of LCZ696) qd for the remaining seven weeks. Placebo of Olmesartan 20 mg capsule once daily also will be taken.	Patients will be treated with Olmesartan 20 mg for eight weeks once daily along with placebo of LCZ696 tablets once daily.
Measure Participants	55	79	74
Hour 1	-7.93 (10.377)	-7.38 (8.786)	-5.99 (11.811)
Hour 2	-8.47 (12.343)	-10.19 (10.836)	-10.49 (12.803)
Hour 3	-9.24 (13.445)	-9.90 (11.353)	-9.28 (11.828)
Hour 4	-6.86 (13.397)	-8.65 (11.740)	-9.80 (12.802)
Hour 5	-5.27 (14.782)	-10.79 (12.123)	-8.54 (15.816)
Hour 6	-7.83 (12.628)	-11.47 (13.154)	-5.55 (14.870)
Hour 7	-7.15 (13.876)	-9.13 (12.990)	-6.23 (14.911)
Hour 8	-8.00 (11.858)	-8.90 (11.220)	-7.44 (13.863)
Hour 9	-8.88 (8.732)	-9.56 (12.309)	-6.83 (13.290)
Hour 10	-6.89 (10.063)	-8.14 (11.244)	-7.07 (13.808)
Hour 11	-5.22 (12.401)	-8.69 (12.989)	-5.41 (12.983)
Hour 12	-402 (13.637)	-7.39 (13.722)	-5.64 (12.158)
Hour 13	-6.84 (12.616)	-6.33 (10.802)	-6.69 (14.822)
Hour 14	-4.34 (12.057)	-6.73 (11.751)	-3.97 (14.844)
Hour 15	-4.53 (13.244)	-5.51 (10.473)	-3.85 (11.421)
Hour 16	-3.91 (11.469)	-7.20 (10.179)	-2.60 (11.997)
Hour 17	-6.68 (11.774)	-7.21 (10.460)	-4.43 (11.789)
Hour 18	-5.87 (12.152)	-6.94 (10.904)	-6.36 (11.225)
Hour 19	-5.32 (9.200)	-7.61 (11.841)	-3.94 (11.700)
Hour 20	-5.17 (16.028)	-10.45 (10.969)	-3.06 (10.965)
Hour 21	-6.97 (12.581)	-9.44 (9.303)	-6.33 (12.257)
Hour 22	-7.57 (11.891)	-11.37 (10.507)	-6.61 (12.324)
Hour 23	-6.12 (13.266)	-9.95 (10.374)	-9.89 (15.553)
Hour 24	-5.23 (10.793)	-8.62 (10.066)	-7.19 (10.504)

8. Secondary Outcome

Title	Sub-group Analysis for Change From Baseline in Mean Ambulatory Systolic Blood Pressure in Non-dippers.
Description	Twenty four hour ABPM was performed twice duirng the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. Dippers were defined as participants who showed a decrease of at least 10% in maSBP during the night (10pm-6am) compared with the daytime level. A negative change from baseline indicates improvement
Time Frame	baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

A subset of participants, who participated in ambulatory blood pressure monitoring, was analyzed

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	Olmesartan 20 mg
Arm/Group Description	Patients will be treated with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily(qd) for eight weeks along with placebo of Olmesartan 20 mg capsule once daily.	Patients will start with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily (qd) for one week, thereafter all patients in the treatment group will be up-titrated to two LCZ696 200 mg tablets (400 mg of LCZ696) qd for the remaining seven weeks. Placebo of Olmesartan 20 mg capsule once daily also will be taken.	Patients will be treated with Olmesartan 20 mg for eight weeks once daily along with placebo of LCZ696 tablets once daily.
Measure Participants	165	156	148
Hour 1	-11.29 (15.196)	-10.38 (15.257)	-9.37 (16.751)
Hour 2	-10.51 (16.652)	-11.07 (17.183)	-10.26 (16.202)
Hour 3	-10.03 (15.654)	-9.82 (18.755)	-9.10 (17.448)
Hour 4	-8.79 (17.070)	-5.77 (17.588)	-7.55 (19.225)
Hour 5	-7.84 (17.290)	-8.15 (16.984)	-6.40 (19.817)
Hour 6	-8.71 (16.700)	-7.77 (17.722)	-6.51 (19.439)
Hour 7	-9.07 (17.599)	-8.27 (19.157)	-6.93 (17.751)
Hour 8	-11.07 (16.115)	-8.30 (16.824)	-6.36 (18.156)
Hour 9	-10.31 (16.749)	-10.65 (15.636)	-8.70 (18.304)
Hour 10	-11.48 (16.782)	-10.68 (17.256)	-7.55 (18.870)
Hour 11	-10.01 (15.182)	-8.96 (19.195)	-9.49 (17.537)
Hour 12	-12.37 (15.745)	-11.55 (18.456)	-8.25 (17.806)
Hour 13	-13.49 (17.706)	10.64 (19.736)	-9.82 (18.908)
Hour 14	-13.20 (16.747)	-13.34 (18.467)	-10.24 (17.972)
Hour 15	-14.01 (17.729)	-11.95 (16.789)	-12.62 (16.855)
Hour 16	-15.15 (15.683)	-14.04 (15.090)	-12.52 (15.137)
Hour 17	-14.00 (16.145)	-14.71 (16.069)	-11.71 (17.849)
Hour 18	-15.93 (16.180)	-15.37 (14.999)	-9.97 (17.116)
Hour 19	-16.45 (16.800)	-16.04 (15.968)	-10.37 (15.684)
Hour 20	-15.29 (16.220)	-14.20 (16.727)	-10.90 (15.129)
Hour 21	-14.10 (15.413)	-15.26 (17.307)	-10.52 (16.818)
Hour 22	-13.97 (15.504)	-12.79 (14.252)	-10.67 (17.877)
Hour 23	-11.91 (15.622)	-9.55 (17.616)	-10.77 (15.363)
Hour 24	-13.07 (15.572)	-11.81 (16.006)	-7.57 (15.992)

9. Secondary Outcome

Title	Sub-group Analysis for Change From Baseline in Mean Ambulatory Diastolic Blood Pressure in Non-dippers.
Description	Twenty four hour ABPM was performed twice duirng the study at baseline and week 8. The second ABPM assessment was performed only in participants who had successfully completed the ABPM assessment at baseline. Dippers were defined as participants who showed a decrease of at least 10% in maSBP during the night (10pm-6am) compared with the daytime level. A negative change from baseline indicates improvement
Time Frame	baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

A subset of participants, who participated in ambulatory blood pressure monitoring, was analyzed

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	Olmesartan 20 mg
Arm/Group Description	Patients will be treated with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily(qd) for eight weeks along with placebo of Olmesartan 20 mg capsule once daily.	Patients will start with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily (qd) for one week, thereafter all patients in the treatment group will be up-titrated to two LCZ696 200 mg tablets (400 mg of LCZ696) qd for the remaining seven weeks. Placebo of Olmesartan 20 mg capsule once daily also will be taken.	Patients will be treated with Olmesartan 20 mg for eight weeks once daily along with placebo of LCZ696 tablets once daily.
Measure Participants	165	156	148
Hour 1	-5.93 (9.153)	-6.57 (10.350)	-4.57 (10.648)
Hour 2	-5.41 (10.593)	-551 (11.655)	-5.49 (11.892)
Hour 3	-3.95 (11.359)	-4.20 (12.472)	-4.44 (12.069)
Hour 4	-3.68 (13.107)	-3.53 (11.966)	-4.70 (12.290)
Hour 5	-3.53 (13.159)	-3.14 (12.208)	-3.81 (13.309)
Hour 6	-4.10 (12.180)	-3.55 (10.888)	-2.94 (13.162)
Hour 7	-4.85 (12.321)	-3.31 (12.281)	-2.71 (13.000)
Hour 8	-6.07 (11.764)	-2.22 (11.449)	-3.44 (12.022)
Hour 9	-4.34 (11.489)	-4.78 (10.645)	-4.54 (12.454)
Hour 10	-5.53 (10.639)	-4.48 (10.549)	-3.57 (12.906)
Hour 11	-4.53 (10.520)	-4.10 (11.889)	-5.51 (13.254)
Hour 12	-5.43 (10.795)	-4.42 (11.973)	-4.50 (11.743)
Hour 13	-5.57 (12.269)	-5.01 (13.670)	-6.04 (12.832)
Hour 14	-6.18 (12.291)	-5.91 (12.409)	-5.26 (12.249)
Hour 15	-7.29 (12.351)	-5.95 (11.443)	-7.52 (12.395)
Hour 16	-7.68 (12.231)	-7.26 (10.726)	-6.96 (11.524)
Hour 17	-7.28 (12.097)	-7.84 (11.479)	-6.14 (12.302)
Hour 18	-8.38 (11.421)	-8.81 (10.385)	-5.28 (12.401)
Hour 19	-9.02 (11.661)	-8.77 (10.560)	-5.20 (11.211)
Hour 20	-8.92 (11.687)	-7.12 (10.020)	-5.80 (11.234)
Hour 21	-8.05 (10.480)	-7.24 (12.056)	-6.49 (12.078)
Hour 22	-7.16 (10.060)	-6.55 (8.317)	-5.65 (11.711)
Hour 23	-6.34 (10.752)	-5.19 (11.593)	-6.26 (9.552)
Hour 24	-5.86 (9.930)	-6.05 (9.926)	-4.96 (9.716)

10. Secondary Outcome

Title	Number of Patients Achieving Successful Blood Pressure Control
Description	Successful blood pressure control is defined as msSBP <140 mmHg and msDBP <90 mmHg.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Participants from the full analysis set (FAS), who had both baseline and endpoint, were included in the analysis. The FAS included all participants who received study medication and had post baseline BP assessments.

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	Olmesartan 20 mg
Arm/Group Description	Patients will be treated with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily(qd) for eight weeks along with placebo of Olmesartan 20 mg capsule once daily.	Patients will start with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily (qd) for one week, thereafter all patients in the treatment group will be up-titrated to two LCZ696 200 mg tablets (400 mg of LCZ696) qd for the remaining seven weeks. Placebo of Olmesartan 20 mg capsule once daily also will be taken.	Patients will be treated with Olmesartan 20 mg for eight weeks once daily along with placebo of LCZ696 tablets once daily.
Measure Participants	477	469	481
Number [Number of participants]	256 53.4%	270 57.2%	235 48.6%

11. Secondary Outcome

Title	Change From Baseline in Ambulatory Pulse Pressure
Description	Ambulatory pulse pressure (PP) is calculated by hourly ambulatory SBP and hourly ambulatory DBP over a 24-hour period.
Time Frame	baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

Participants from the full analysis set (FAS), who had both baseline and endpoint, were included in the analysis. The FAS included all participants who received study medication and had post baseline BP assessments.

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	Olmesartan 20 mg
Arm/Group Description	Patients will be treated with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily(qd) for eight weeks along with placebo of Olmesartan 20 mg capsule once daily.	Patients will start with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily (qd) for one week, thereafter all patients in the treatment group will be up-titrated to two LCZ696 200 mg tablets (400 mg of LCZ696) qd for the remaining seven weeks. Placebo of Olmesartan 20 mg capsule once daily also will be taken.	Patients will be treated with Olmesartan 20 mg for eight weeks once daily along with placebo of LCZ696 tablets once daily.
Measure Participants	188	184	182
Least Squares Mean (Standard Error) [mmHg]	-5.78 (0.23)	-5.98 (0.23)	-4.58 (0.23)

12. Secondary Outcome

Title	Number of Responders
Description	Responders are patients with msSBP response (<140 mmHg or ≥20 mmHg reduction from baseline) and msDBP response (<90 mmHg or ≥10 mmHg reduction from baseline)
Time Frame	baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

Participants from the full analysis set (FAS), who had both baseline and endpoint, were included in the analysis. The FAS included all participants who received study medication and had post baseline BP assessments

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	Olmesartan 20 mg
Arm/Group Description	Patients will be treated with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily(qd) for eight weeks along with placebo of Olmesartan 20 mg capsule once daily.	Patients will start with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily (qd) for one week, thereafter all patients in the treatment group will be up-titrated to two LCZ696 200 mg tablets (400 mg of LCZ696) qd for the remaining seven weeks. Placebo of Olmesartan 20 mg capsule once daily also will be taken.	Patients will be treated with Olmesartan 20 mg for eight weeks once daily along with placebo of LCZ696 tablets once daily.
Measure Participants	477	469	481
Number [Participants]	312 65.1%	314 66.5%	290 59.9%

13. Secondary Outcome

Title	Number of Patients With Adverse Events, Serious Adverse Events, and Death as Assessment of Safety and Tolerability
Description	Participants were monitored for adverse events, serious adverse events and deaths throughout the study.
Time Frame	baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

Safety Set (SAF): All patients who received at least one dose of double-blind trial medication. Patients were analyzed according to the treatment they received.

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	Olmesartan 20 mg
Arm/Group Description	Patients will be treated with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily(qd) for eight weeks along with placebo of Olmesartan 20 mg capsule once daily.	Patients will start with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily (qd) for one week, thereafter all patients in the treatment group will be up-titrated to two LCZ696 200 mg tablets (400 mg of LCZ696) qd for the remaining seven weeks. Placebo of Olmesartan 20 mg capsule once daily also will be taken.	Patients will be treated with Olmesartan 20 mg for eight weeks once daily along with placebo of LCZ696 tablets once daily.
Measure Participants	478	472	484
Adverse events (non-serious and serious	143 29.9%	132 28%	134 27.7%
Serious adverse events	5 1%	3 0.6%	6 1.2%
Deaths	0 0%	0 0%	0 0%

Adverse Events

Arm/Group Title	LCZ696 200 mg		LCZ696 400 mg		Olmesartan 20 mg
Arm/Group Description	Patients will be treated with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily(qd) for eight weeks along with placebo of Olmesartan 20 mg capsule once daily		Patients will start with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily (qd) for one week, thereafter all patients in the treatment group will be up-titrated to two LCZ696 200 mg tablets (400 mg of LCZ696) qd for the remaining seven weeks. Placebo of Olmesartan 20 mg capsule once daily also will be taken.		Patients will be treated with Olmesartan 20 mg for eight weeks once daily along with placebo of LCZ696 tablets once daily
All Cause Mortality
	LCZ696 200 mg		LCZ696 400 mg		Olmesartan 20 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	LCZ696 200 mg		LCZ696 400 mg		Olmesartan 20 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/478 (1%)		3/472 (0.6%)		6/484 (1.2%)
Cardiac disorders
ACUTE CORONARY SYNDROME	0/478 (0%)		0/472 (0%)		1/484 (0.2%)
ANGINA PECTORIS	0/478 (0%)		0/472 (0%)		1/484 (0.2%)
ATRIAL FIBRILLATION	0/478 (0%)		0/472 (0%)		1/484 (0.2%)
Hepatobiliary disorders
BILE DUCT STONE	1/478 (0.2%)		0/472 (0%)		0/484 (0%)
CHOLELITHIASIS	1/478 (0.2%)		0/472 (0%)		0/484 (0%)
Infections and infestations
DENGUE FEVER	0/478 (0%)		0/472 (0%)		1/484 (0.2%)
GASTROENTERITIS	0/478 (0%)		1/472 (0.2%)		0/484 (0%)
Investigations
ALANINE AMINOTRANSFERASE INCREASED	1/478 (0.2%)		0/472 (0%)		0/484 (0%)
ASPARTATE AMINOTRANSFERASE INCREASED	1/478 (0.2%)		0/472 (0%)		0/484 (0%)
BLOOD BILIRUBIN INCREASED	0/478 (0%)		0/472 (0%)		1/484 (0.2%)
Musculoskeletal and connective tissue disorders
SPINAL OSTEOARTHRITIS	0/478 (0%)		1/472 (0.2%)		0/484 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
THYROID NEOPLASM	0/478 (0%)		1/472 (0.2%)		0/484 (0%)
Renal and urinary disorders
CALCULUS URETERIC	1/478 (0.2%)		0/472 (0%)		0/484 (0%)
Skin and subcutaneous tissue disorders
PRURITUS	1/478 (0.2%)		0/472 (0%)		0/484 (0%)
Vascular disorders
HYPERTENSION	0/478 (0%)		0/472 (0%)		1/484 (0.2%)
Other (Not Including Serious) Adverse Events
	LCZ696 200 mg		LCZ696 400 mg		Olmesartan 20 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	66/478 (13.8%)		63/472 (13.3%)		66/484 (13.6%)
Infections and infestations
UPPER RESPIRATORY TRACT INFECTION	15/478 (3.1%)		5/472 (1.1%)		8/484 (1.7%)
Investigations
BLOOD GLUCOSE INCREASED	5/478 (1%)		10/472 (2.1%)		13/484 (2.7%)
Metabolism and nutrition disorders
HYPERLIPIDAEMIA	16/478 (3.3%)		22/472 (4.7%)		21/484 (4.3%)
HYPERURICAEMIA	14/478 (2.9%)		13/472 (2.8%)		16/484 (3.3%)
Nervous system disorders
DIZZINESS	8/478 (1.7%)		11/472 (2.3%)		3/484 (0.6%)
HEADACHE	6/478 (1.3%)		4/472 (0.8%)		10/484 (2.1%)
Respiratory, thoracic and mediastinal disorders
COUGH	11/478 (2.3%)		5/472 (1.1%)		3/484 (0.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.